Myocardial ischemia and coronary artery disease are among the most important causes of death and disability in the U.S. Despite the intense investigation of the mechanisms of ischemic preconditioning, it has been difficult to translate that beneficial process to the clinical setting. One limitation is to discover models that actually enhance angiogenesis and collateral formation, which is the most effective way of protecting ischemic myocardium, and which is central to the current project. Therefore, we developed a swine model of repetitive episodes of low-flow coronary stenosis, which reproduces the conditions of transient and repeated ischemic episodes found in patients with ischemic heart disease, which displays collateral development through angiogenesis. Secret frizzled related protein 2 (sFRP2) was found as the most up-regulated gene uniquely in this model, indicating that this protein is potentially a novel mediator of cardiac protection conferred by chronic ischemia, as occurs in patients with coronary disease. Our preliminary data indicate that over expression of sFRP2 significantly increases angiogenesis and collateral blood flow and reduces the size of infarctions in acute myocardial ischemia. This over expression also improves the remodeling process after permanent coronary artery occlusion through two major novel mechanisms, by promoting cell survival through an uncovered endoplasmic reticulum (ER) stress response signaling, and by increasing the collateral blood flow through angiogenesis. The goal of this grant proposal is to investigate the mechanisms involved in cardiac protection by sFRP2 by using both a transgenic and knockout mouse model as well as a large animal model. We will first test our Hypothesis A that over-expression of sFRP2 in the heart will promote cardiac cell survival through a novel mechanism by enhancing the response to ER stress via the activation of ATF6 /GRP78 signaling. Importantly, we will test Hypothesis B that sFRP2 protects cardiac remodeling after chronic MI through 2 mechanisms. The first mechanism involves induction of angiogenesis/arteriogenesis, and the second mechanism involves improved cell survival through the ER stress pathway via the activation of ATF6/GRP78 signaling, Fibrosis will be a secondary and less important mechanism in cardiac remodeling. Clearly the ability to define such pathways, and thus to potentially bolster myocardial repair after injury, through a combination of arteriogenesis and protection of the myocyte through sFRP2 signaling, has enormous clinical ramifications for the treatment of both myocardial infarction and heart failure, the leading causes of death and disability in our society.